CN101220084B - Production method of polyglycol modifying ferric iron deuterohemin short peptide compound - Google Patents
Production method of polyglycol modifying ferric iron deuterohemin short peptide compound Download PDFInfo
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- CN101220084B CN101220084B CN2008100503077A CN200810050307A CN101220084B CN 101220084 B CN101220084 B CN 101220084B CN 2008100503077 A CN2008100503077 A CN 2008100503077A CN 200810050307 A CN200810050307 A CN 200810050307A CN 101220084 B CN101220084 B CN 101220084B
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Abstract
The invention belongs to the biotechnology field, which particularly relates to a deuterohemin short peptide compound modified by the Monomethoxy-Polyethylene Glycol Succinimidyl Ester derivatives and the preparation method for the compound, which adds phosphate buffer into the water solution prepared by a deuterohemin 6-mer peptide, and then reacts by adding the solid powder of active Polyethylene Glycol derivatives or the acetonitrile solution of the Polyethylene Glycol derivatives and obtains the deuterohemin 6-mer peptide modified by the Polyethylene Glycol by chromatographic separating of the reaction mixture with the reversed-phase high performance Liquid Chromatography. The deuterohemin 6-mer peptide modified by the Polyethylene Glycol of the invention can basically maintain the biological activity of the deuterohemin 6-mer peptide, and has better stability than the deuterohemin 6-mer peptide without any modification. The preparation method of the deuterohemin 6-mer peptide modified by the Polyethylene Glycol of the invention is simple and easy to operate, while the structure general formula of the deuterohemin 6-mer peptide modified by the Polyethylene Glycol is shown on the right, wherein, R stands for a DhHP-6 molecule eliminating an NH2.
Description
Technical field
The invention belongs to biological technical field, be specifically related to a kind of preparation method of Deuterohemin short-peptide compound of mono methoxy polyethylene glycol succinimide ester derivative modification.
Background of invention
(Deuterohemin-Ala-His-Thr-Val-Glu-Lys is to be foundation with little enzyme and natural ascorbate peroxidase enzymatic structure DhHP-6) to inferior sanguinin six peptides, and a kind of small peptide that contains deuterohemin of design is a kind of mimics of peroxidase preferably.This small peptide analogue enztme molecular weight can develop into anti-oxidation medicine efficiently less than 3000.But its bioavailability is low, is subject to proteasome degradation.
The derivative of mono methoxy polyethylene glycol succinimide ester is to be main chain with the polyoxyethylene glycol, and has the macromolecular compound of a methoxyl group end group and an activatory succinimide ester terminal.Wherein, polyoxyethylene glycol (PEG) is the nontoxic polymer of a kind of wetting ability, biocompatibility, and its general formula is H (OCH
2CH)
nOH is n 〉=4 wherein, and its molecular weight is that 200 to 20000 dalton do not wait.FDA (Food and Drug Adminstration) (FDA) has ratified PEG as auxiliary material, at food, and makeup, and intravenous injection, the application in the medicament production such as oral and percutaneous dosing.Simultaneously, the characteristic that it can excrete by liver kidney approach makes it become highly desirable pharmaceutical excipient.Studies have shown that in a large number: after the PEG of mono methoxy form and protein and/or the chemistry of peptides coupling, the energy significant prolongation latter's biological action, many PEG-albumen and/or peptide conjugate can be avoided by protease hydrolyzed, and/or the immunogenicity of self is reduced.PEG and derivative thereof have obtained using widely in a lot of commercial medicines as the carrier of pharmaceutical preparation.
The most frequently used method of preparation protein and/or peptide and polyethylene glycol conjugate is to utilize the electrophilic group of PEG activation back formation and the amino on the protein/polypeptide to react, can be on an albumen/peptide molecule after the reaction covalently bound several polymer chains, the number of polymer chain depends on the chemical property that can supply bonded number of sites, modifier on the protein/polypeptide, the extra proportion of modifier and reaction conditions.
Summary of the invention
The objective of the invention is to deuterohemin six peptides (DhHP-6) are modified with polyoxyethylene glycol (PEG), a kind of preparation method of polyethyleneglycol modified ferric iron Deuterohemin short-peptide compound is provided.
The DhHP-6 molecule has following structural formula (I):
What this patent adopted is present widespread use and commercial activated polyethylene glycol derivative, the structural formula of polyoxyethylene glycol following (II):
The general structure following (III) of the activated polyethylene glycol derivative that this patent adopts:
Wherein the weight-average molecular weight of polyoxyethylene glycol (PEG) is 2000-20000 (corresponding, 44≤n≤447), k=0～3, (molecular weight of polyoxyethylene glycol is too small, its meta-bolites in vivo may be harmful, is unfavorable for too greatly modifying, and may cause the peptide medicament inactivation simultaneously);
By nucleophilic substitution reaction, prepare a kind of polyethyleneglycol modified deuterohemin six peptides, its general structure following (IV):
An amino (NH is removed in the R representative
2) the DhHP-6 molecule, have following structure (V):
The preparation method of the DhHP-6 that the PEG that the present invention describes modifies is as follows:
DhHP-6 is dissolved in the solution that is mixed with 0.5～5mg/ml in the deionized water, to wherein adding pH is 5～8 phosphate buffer soln (PBS), be diluted to 5～10 times of volumes, acetonitrile (ACN) solution that adds polyethyleneglycol derivative or 10～40mg/ml polyethyleneglycol derivative then, temperature of reaction is 0～25 ℃, the mol ratio of polyethyleneglycol derivative and DhHP-6 is 5～20: 1 in the reaction, reaction times is 0.5～4 hour, reaction finishes back glycine termination reaction, pick out the DhHP-6 elution peak that PEG modifies by RPLC, rotation is evaporated to no obvious bubble generation under decompression under 40 ℃, with the raffinate freeze-drying, get final product the DhHP-6 solid modified of PEG.
The moving phase of RPLC post is A:H
2(contain 0.5% trifluoroacetic acid (TFA, v/v)), the acetonitrile solution of B:90% (contains 0.5% trifluoroacetic acid (TFA, v/v)) to O; Concentration gradient is a B phase 40%～60%, time is 40 minutes, (concentration is by machine control itself, and during original state, the volume ratio of water and acetonitrile is 6: 4, in the experimentation, machine is the acetonitrile phase volume ratio and reduce the water volume ratio of will raising automatically in the kind in 40 minutes in the time of setting here), wherein the elution peak that occurs about 11 minutes is the DhHP-6 peak, and the elution peak that occurs about 15 minutes is the peak of the DhHP-6 of PEG modification.
Preparation feedback is as shown in the formula carrying out:
R-NH wherein
2Represent DhHP-6, the weight-average molecular weight of polyoxyethylene glycol (PEG) is 2000～20000 (44≤n≤447), k=0～3, and an amino (NH is removed in the R representative
2) the DhHP-6 molecule;
Previously described polyethyleneglycol derivative is well-known to those skilled in the art, comprising: methoxy poly (ethylene glycol) succinimide ester or propionic acid methoxy poly (ethylene glycol) succinimide ester or butyric acid methoxy poly (ethylene glycol) succinimide ester etc.
The invention has the advantages that:
1. modifying method of the present invention is easy.Higher yields can be carried out and have to reaction at room temperature both.
2. the purposes of polyethyleneglycol modified DhHP-6 of the present invention is to be used to prepare anti-oxidation medicine, antiaging agent and treat cataractous medicine.
3. polyethyleneglycol modified DhHP-6 of the present invention can keep the anti-oxidant activity of DhHP-6 substantially, and it has better stability than the DhHP-6 of unmodified again simultaneously.
Description of drawings
Fig. 1: be under 390nm detection wavelength, to use Edipse XDB-C among the embodiment 1
18Post is analyzed the tomographic map of the DhHP-6 aqueous solution, and wherein, under specified condition, the DhHP-6 retention time is 11.832min and 12.116min;
Fig. 2: be under 390nm detection wavelength, to use Edipse XDB-C among the embodiment 1
18Post is analyzed the tomographic map of polyethyleneglycol modified DhHP-6, and wherein, under specified condition, polyethyleneglycol modified DhHP-6 retention time is 15.057min;
Fig. 3: be under 390nm detection wavelength, to use Edipse XDB-C among the embodiment 2
18Post is analyzed the tomographic map of modification reaction liquid, and wherein, effusive during 11.887min is DhHP-6, and its peak area is 2734.47, accounts for 31.21% of total peak area; 15.257min the time effusive be polyethyleneglycol modified DhHP-6, its peak area is 6835.72, accounts for 68.79% of total peak area;
Fig. 4: be the flight time mass spectrum figure of DhHP-6 among the embodiment 2, wherein unimodal 1498 the molecular weight with DhHP-6 in 1497.5 places meets;
Fig. 5: be the flight time mass spectrum figure of PEG-DhHP-6 among the embodiment 2, wherein the molecular weight of about 22000 continuous peak and polyethyleneglycol modified DhHP-6 meets.
Embodiment
Embodiment 1:
Methoxy poly (ethylene glycol) succinimide carbonic ether (structure is seen general formula, k=0, the weight-average molecular weight of PEG is 20000, n ≈ 447) is (m-SC-PEG20000) to the modification of deuterohemin six peptides (DhHP-6):
The selection of temperature of reaction: the DhHP-6 pressed powder is dissolved in the deionized water, be mixed with the DhHP-6 deionized water solution of 1mg/ml, get the deionized water solution (1mg/ml) of 4 parts of 0.1ml DhHP-6, phosphate buffered saline buffer (PBS) with pH=7 is diluted to 1ml, (back refers to mol ratio to add 20mg m-SC-PEG20000 respectively, mol ratio approximates (20/20000)/(0.1/1000)=10: 1), fully after the dissolving, place 0 ℃, 4 ℃, 15 ℃, 25 ℃ environment reactions after 1 hour respectively, add the glycine termination reaction.Detect transformation efficiency with RPLC, record its transformation efficiency and be respectively 37.1%, 38.5%, 47.9% and 55.1%, the result shows that along with the rising of temperature of reaction, transformation efficiency is significantly improved, and wherein transformation efficiency is the highest 25 ℃ the time.
The selection of reaction PH: the deionized water solution (1mg/ml) of getting 3 parts of 0.1ml DhHP-6, after being diluted to 1ml with the PBS of pH=7, pH=7.5 and pH=8 respectively, add 20mg m-SC-PEG20000 respectively, fully after the dissolving, place 25 ℃ of environment reactions after 1 hour, add the glycine termination reaction.Detect transformation efficiency with RPLC, record its transformation efficiency and be respectively 55.1%, 57.8% and 59.9%, the result shows that along with the rising of pH value, transformation efficiency is significantly improved, and wherein transformation efficiency is the highest during pH=8.
The selection in reaction times: the deionized water solution (1mg/ml) of getting 4 parts of 0.1ml DhHP-6, after being diluted to 1ml with the phosphate buffered saline buffer (PBS) of pH=8, add 20mg m-SC-PEG20000 respectively, fully after the dissolving, place 25 ℃ of environment, after reacting 0.5h, 1h, 2h and 4h respectively, add the glycine termination reaction.Detect transformation efficiency with RPLC, detect transformation efficiency with RPLC, record its transformation efficiency and be respectively 20.6%, 38.5%, 59.9% and 60.4%, the result shows, prolongation along with the reaction times, transformation efficiency is significantly improved, and reaches maximum conversion rate substantially during to 2 hours, further prolongs the reaction times not see that transformation efficiency has considerable change.
M-SC-PEG20000 is with the selection of the mol ratio of DhHP-6: the deionized water solution (1mg/ml) of getting 4 parts of 0.1ml DhHP-6, after being diluted to 1ml with the phosphate buffered saline buffer (PBS) of pH=8, add 10mg, 20mg, 30mg, 40mg m-SC-PEG20000 (mol ratio of m-SC-PEG20000: DhHP-6 was respectively 5: 1,10: 1,15: 1 and 20: 1) respectively, fully after the dissolving, place 25 ℃ of environment, after reacting 2h respectively, add the glycine termination reaction.Detect transformation efficiency with RPLC, record its transformation efficiency and be respectively 38.1%, 59.9%, 62.4% and 65.7%, the result shows, increase along with the m-SC-PEG20000 charging capacity, transformation efficiency is significantly improved, transformation efficiency has reached the highest when the mol ratio of PEG and DhHP-6 is 10, and the charging capacity that further increases m-SC-PEG20000 does not see that transformation efficiency is significantly increased.
The influence of acetonitrile to reacting: the deionized water solution (1mg/ml) of getting 2 parts of 0.1ml DhHP-6, after being diluted to 0.5ml with the phosphate buffered saline buffer (PBS) of pH=8, add in the solution with 0.5ml acetonitrile dissolved 20mgm-SC-PEG20000, place 25 ℃ of environment, after reacting 2h respectively, add the glycine termination reaction.Detect transformation efficiency with RPLC, record its transformation efficiency and be respectively 59.9% and 65.0%, the result shows that the use of acetonitrile can make transformation efficiency improve 5-10 percentage point.
Embodiment 2: the separation and purification of modified outcome and evaluation
The DhHP-6 pressed powder is dissolved in the deionized water, be mixed with the DhHP-6 deionized water solution of 1mg/ml, get the deionized water solution (1mg/ml) of 0.1ml DhHP-6, after being diluted to 1ml with the phosphate buffered saline buffer (PBS) of pH=8, add 20mg m-SC-PEG20000, after the dissolving, place 25 ℃ of environment fully, behind the reaction 2h, add the glycine termination reaction.
Above-mentioned reaction solution upper prop is separated, and chromatographic condition is as follows:
Chromatographic instrument: BioCAD 700E;
Post specification: prepLC, 25mmModule;
Flow velocity: 10ml/min;
Moving phase: A:H
2(contain 0.5% trifluoroacetic acid (TFA, v/v)), the acetonitrile solution of B:90% (contains 0.5% trifluoroacetic acid (TFA, v/v)) to O;
Concentration gradient: elution time 0-5min, 100%A phase, elution time 5-45min, B phase gradient from 40% to 60%;
Detect wavelength: 390nm;
Collect: every pipe 10ml.
The result obtains two elution peaks, is respectively DhHP-6 and DhHP-6 that PEG modifies, the results are shown in Figure 3.With the corresponding solution of above-mentioned elution peak, detect with flight time mass spectrum.First elution peak correspondence be a molecular weight be 1497.5 unimodal, be DhHP-6, the results are shown in Figure 4.Second elution peak correspondence be a broad peak, its molecular-weight average is about 22000, the DhHP-6 for PEG modifies the results are shown in Figure 5.With the leacheate that obtains 40 ℃ down under the decompression rotation be evaporated to no obvious bubble and produce, with the raffinate freeze-drying, get final product the DhHP-6 solid of PEG modification.
Embodiment 3: the biological activity of modified outcome (than vigor) is measured
With little enzyme that the cytochrome c hydrolysis obtains, M P-9 is as standard control, with xitix (V
C) and H
2O
2Be substrate, measured the peroxidase activity of DhHP-6 and PEG-DhHP-6, wherein DhHP-6 is 4.0 * 10 than work
3U/ μ mol, and the ratio work of PEG-DhHP-6 is 3.1 * 10
3U/ μ mol (the required enzyme amount of definition per minute oxidation 1 μ gVC is a unit of activity U), the results are shown in Table 1: as can be seen from the table, the DhHP-6 that modifies through PEG still has higher activity, illustrates that this modifying method is feasible.
The ratio vigor of table 1:DhHP-6 and PEG-DhHP-6
| Sample | Than vigor (U/ μ mol) | The vigor (100%) of relative MP-9 |
| ?MP-9 | ?4.2×10 3 | 100 |
| ?DhHP-6 | ?4.0×10 3 | 95 |
| ?PEG-DhHP-6 | ?3.1×10 3 | 77 |
The vitro enzyme stability study of embodiment 4:PEG-DhHP-6
Get papoid solution (PH=6.5) 2.7ml of 0.1% (w/w), add the sample of 0.3ml (1mg/ml) DhHP-6 and PEG-DhHP-6 respectively, 40 ℃ of water-baths, in 0,0.5,1,2, the 4h 0.3ml that takes a sample, the working sample biological activity.The result shows: DhHP-6 is active in 1 hour to be reduced to originally below 50% rapidly, only drops to original 70% and PEG-DhHP-6 is active in 1 hour.Therefore, polyethyleneglycol modified DhHP-6 can obviously increase the ability that DhHP-6 resists papain hydrolysis.
Embodiment 5:
With with embodiment 1 in have the activated polyethylene glycol derivative of different polyethylene glycol backbone molecular weight, methoxy poly (ethylene glycol) succinimide carbonic ether 2000 (m-SC-PEG2000, structure is seen general formula, k=0, the weight-average molecular weight of PEG is 2000, n ≈ 44), methoxy poly (ethylene glycol) succinimide carbonic ether 5000 (m-SC-PEG5000, structure is seen general formula, k=0, the weight-average molecular weight of PEG is 5000, n ≈ 112) or methoxy poly (ethylene glycol) succinimide carbonic ether 10000 (m-SC-PEG10000, structure is seen general formula, k=0, the weight-average molecular weight of PEG is 10000, n ≈ 226), replace the m-SC-PEG20000 in the example 1, obtain to embodiment 1-4 in similar result.
Embodiment 6:
With propionic acid methoxy poly (ethylene glycol) succinimide ester 2000 (mPEG-SPA-2000, structure is seen general formula, k=2, the weight-average molecular weight of PEG is 2000, n ≈ 44), propionic acid methoxy poly (ethylene glycol) succinimide ester 5000 (mPEG-SPA-5000, structure is seen general formula, k=2, the weight-average molecular weight of PEG is 5000, n ≈ 112), and propionic acid methoxy poly (ethylene glycol) succinimide ester 10000 (mPEG-SPA-10000, structure is seen general formula, k=2, the weight-average molecular weight of PEG is 10000, n ≈ 226) or propionic acid methoxy poly (ethylene glycol) succinimide ester 20000 (mPEG-SPA-20000, structure is seen general formula, k=2, the weight-average molecular weight of PEG is 20000, n ≈ 447) replace the m-SC-PEG20000 among the embodiment 1, obtain to example 1-4 in similar result.
Embodiment 7:
With butyric acid methoxy poly (ethylene glycol) succinimide ester 2000 (mPEG-SBA-2000, structure is seen general formula, k=3, the weight-average molecular weight of PEG is 2000, n ≈ 44), butyric acid methoxy poly (ethylene glycol) succinimide ester 5000 (mPEG-SBA-5000, structure is seen general formula, k=3, the weight-average molecular weight of PEG is 5000, n ≈ 112), and butyric acid methoxy poly (ethylene glycol) succinimide ester 10000 (mPEG-SBA-10000, structure is seen general formula, k=3, the weight-average molecular weight of PEG is 10000, n ≈ 226) or butyric acid methoxy poly (ethylene glycol) succinimide ester 20000 (mPEG-SBA-20000, structure is seen general formula, k=3, the weight-average molecular weight of PEG is 10000, n ≈ 447) replace the m-SC-PEG20000 among the embodiment 1, obtain to example 1-4 in similar result.
Embodiment 8:
With acetate methoxy poly (ethylene glycol) succinimide ester 2000 (mPEG-SCM-2000, structure is seen general formula, k=1, the weight-average molecular weight of PEG is 2000, n ≈ 44), acetate methoxy poly (ethylene glycol) succinimide ester 5000 (mPEG-SCM-5000, structure is seen general formula, k=1, the weight-average molecular weight of PEG is 5000, n ≈ 112), acetate methoxy poly (ethylene glycol) succinimide ester 10000 (mPEG-SCM-10000, structure is seen general formula, k=1, and the weight-average molecular weight of PEG is 10000, n ≈ 226) or acetate methoxy poly (ethylene glycol) succinimide ester 20000 (mPEG-SCM-20000, structure is seen general formula, k=1, and the weight-average molecular weight of PEG is 10000, n ≈ 447) m-SC-PEG20000 among the replacement embodiment 1, the polyethyleneglycol modified DhHP-6 that also obtains of reaction, but because mPEG-SCM is highly susceptible to hydrolysis, reaction conversion ratio has only half with the transformation efficiency of other reactant gained under the equal conditions.
Claims (5)
1. the preparation method of a polyethyleneglycol modified ferric iron Deuterohemin short-peptide compound, the steps include: deuterohemin six peptides, its structure is suc as formula shown in (I), be dissolved in the solution that is mixed with 0.5～5mg/ml in the deionized water, to wherein adding pH is 5～8 phosphate buffer soln, be diluted to 5～10 times of volumes, the acetonitrile solution that adds 10～40mg/ml polyethyleneglycol derivative then, wherein the structure of polyethyleneglycol derivative is suc as formula shown in (III), temperature of reaction is 0～25 ℃, reaction times is 0～54 hour, reaction finishes back glycine termination reaction, the mol ratio of polyethyleneglycol derivative and deuterohemin six peptides is 5～20: 1 in the reaction, picks out Pegylation deuterohemin six peptide elution peaks by RPLC, the elution peak decompression is rotated down be evaporated to no obvious bubble generation, with the raffinate freeze-drying, promptly get polyethyleneglycol modified deuterohemin six peptides, its structural formula is shown in (IV)
Wherein, 44≤n≤447, k=0-3
Wherein the weight-average molecular weight of polyoxyethylene glycol is 2000～20000, k=0～3, and the DhHP-6 of an amino is removed in the R representative, has as (V) formula structure:
2. the preparation method of polyethyleneglycol modified ferric iron Deuterohemin short-peptide compound as claimed in claim 1, it is characterized in that: polyethyleneglycol derivative is the methoxy poly (ethylene glycol) succinimdyl carbonate.
3. the preparation method of polyethyleneglycol modified ferric iron Deuterohemin short-peptide compound as claimed in claim 1, it is characterized in that: polyethyleneglycol derivative is a propionic acid methoxy poly (ethylene glycol) succinimide ester.
4. the preparation method of polyethyleneglycol modified ferric iron Deuterohemin short-peptide compound as claimed in claim 1, it is characterized in that: polyethyleneglycol derivative is a butyric acid methoxy poly (ethylene glycol) succinimide ester.
5. the preparation method of polyethyleneglycol modified ferric iron Deuterohemin short-peptide compound as claimed in claim 1, it is characterized in that: polyethyleneglycol derivative is an acetate methoxy poly (ethylene glycol) succinimide ester.
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| CN103965287A (en) * | 2014-05-07 | 2014-08-06 | 吉林大学 | Deuterohemin-beta-Ala-His-Lys(DhHP-3), and preparation method and application thereof |
| CN106220843B (en) * | 2016-07-29 | 2018-07-31 | 中国科学院过程工程研究所 | A kind of polyethyleneglycol modified dose and its preparation method and application containing Lin Ben diquines functional group |
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